Background: Thyroid cancer is one of the fastest growing cancer diagnoses in the United States. Non-medullary thyroid cancer accounts for 95% of all thyroid cancer cases. Up to 8% of all non-medullary thyroid cancers are hereditary. Familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic disease. No susceptibility gene for FNMTC has been identified. The best approach for screening at risk family members for FNMTC is unknown. This protocol is designed to determine the natural history and best screening strategy for FNMTC, and to identify susceptibility gene(s) for FNMTC. Summary: This is a prospective study of individuals with or at risk for non-medullary thyroid cancer. Individuals will be studied over time within the context of their families in order to quantify prospective risks of cancers in family members, to establish the natural history of FNMTC, define the spectrum of diseases within the families, to identify precursor states, to try to assess the contribution of genetic and environmental components of risk, and to develop effective screening strategies. Our initial genomic analysis of human familial and sporadic cases of non-medullary thyroid cancer have identified several dysregulated genes which have important regulatory roles in thyroid cancer cell proliferation and cell cycle progression. We will further characterize the mechanism of gene expression regulation in FNMTC tumor samples and determine if these genes are modifier and or susceptibility genes. Germline genetic studies to identify the susceptibility gene(s) for FNMTC are also underway using a variety of genetic approaches including linkage, association, copy number variation search, and exome/whole-genome sequencing to identify both common and rare genetic variants.